research on covid vaccine side effects

Study Largely Confirms Known, Rare COVID-19 Vaccine Side Effects

By Kate Yandell

Posted on February 27, 2024

SciCheck Digest

An international study of around 99 million people confirmed known serious side effects of COVID-19 vaccination. It also identified a possible relationship between the first dose of the Moderna vaccine and a small risk of a neurological condition. Social media posts about the study left out information on the vaccines’ benefits and the rarity of the side effects.

More than  half a billion doses of COVID-19 vaccines have now been administered in the U.S. and only a few, very rare, safety concerns have emerged. The vast majority of people experience only minor, temporary side effects such as pain at the injection site, fatigue, headache, or muscle pain — or no side effects at all. As the Centers for Disease Control and Prevention has said , these vaccines “have undergone and will continue to undergo the most intensive safety monitoring in U.S. history.”

A small number of severe allergic reactions known as anaphylaxis, which are expected with any vaccine, have occurred with the authorized and approved COVID-19 vaccines. Fortunately, these reactions are rare, typically occur within minutes of inoculation and can be treated. Approximately 5 per million people vaccinated have experienced anaphylaxis after a COVID-19 vaccine, according  to the CDC.

To make sure serious allergic reactions can be identified and treated, all people receiving a vaccine should be observed for 15 minutes after getting a shot, and anyone who has experienced anaphylaxis or had any kind of immediate allergic reaction to any vaccine or injection in the past should be monitored for a half hour. People who have had a serious allergic reaction to a previous dose or one of the vaccine ingredients should not be immunized. Also, those who shouldn’t receive one type of COVID-19 vaccine should be monitored for 30 minutes after receiving a different type of vaccine.

There is evidence that the Pfizer/BioNTech and Moderna mRNA vaccines may rarely cause inflammation of the heart muscle (myocarditis) or of the surrounding lining (pericarditis), particularly in male adolescents and young adults .

Based on data collected through August 2021, the reporting rates of either condition in the U.S. are highest in males 16 to 17 years old after the second dose (105.9 cases per million doses of the Pfizer/BioNTech vaccine), followed by 12- to 15-year-old males (70.7 cases per million). The rate for 18- to 24-year-old males was 52.4 cases and 56.3 cases per million doses of Pfizer/BioNTech and Moderna vaccines, respectively.

Health officials have emphasized that vaccine-related myocarditis and pericarditis cases are rare and the benefits of vaccination still outweigh the risks. Early evidence suggests these myocarditis cases are less severe than typical ones. The CDC has also noted that most patients who were treated “responded well to medicine and rest and felt better quickly.”

The Johnson & Johnson vaccine has been linked to an  increased risk of rare blood clots combined with low levels of blood platelets, especially in women ages 30 to 49 . Early symptoms of the condition, which is known as thrombosis with thrombocytopenia syndrome, or TTS, can appear as late as three weeks after vaccination and  include  severe or persistent headaches or blurred vision, leg swelling, and easy bruising or tiny blood spots under the skin outside of the injection site.

According to the CDC, TTS has occurred in around 4 people per million doses administered. As of early April ,  the syndrome has been confirmed in 60 cases, including nine deaths, after more than 18.6 million doses of the J&J vaccine. Although TTS remains rare, because of the availability of mRNA vaccines, which are not associated with this serious side effect, the FDA on May 5 limited authorized use of the J&J vaccine to adults who either couldn’t get one of the other authorized or approved COVID-19 vaccines because of medical or access reasons, or only wanted a J&J vaccine for protection against the disease. Several months earlier, on Dec. 16, 2021 ,  the CDC had recommended the Pfizer/BioNTech and Moderna shots over J&J’s.

The J&J vaccine has also been linked to an increased risk of Guillain-Barré Syndrome, a rare disorder in which the immune system attacks nerve cells.  Most people  who develop GBS fully recover, although some have permanent nerve damage and the condition can be fatal.

Safety surveillance data suggest that compared with the mRNA vaccines, which have not been linked to GBS, the J&J vaccine is associated with 15.5 additional GBS cases per million doses of vaccine in the three weeks following vaccination. Most reported cases following J&J vaccination have occurred in men 50 years old and older.

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COVID-19 vaccines — like all  vaccines  and other medical products — come with side effects, including  serious side effects  in rare cases. The vaccines were rolled out to protect people from a novel virus that has  killed  millions of people globally and would likely have killed millions more without the arrival of the vaccines. There is a broad consensus from experts and governmental health agencies that the benefits of COVID-19 vaccination outweigh the risks.

Researchers have  scrutinized  the COVID-19 vaccines’ safety and continue to do so. A  study  published Feb. 12 in the journal Vaccine reported on an international group of more than 99 million people who received COVID-19 vaccines, primarily finding links to known rare side effects. The study largely focused on the Pfizer/BioNTech and Moderna vaccines, which have been  widely given  in the U.S., as well as the AstraZeneca vaccine, which was  never authorized  in the U.S.

“What we take away, is that the Covid-19 vaccination campaigns have been very effective in preventing severe disease,” study co-author  Anders Hviid , head of the department of epidemiology research at the Statens Serum Institut in Denmark, told us in an email. “The few serious side effects that we have observed in this and other studies have been rare.”

Many popular posts on social media have shared results from the study, some lacking the context that the identified  health problems are rare , that most aren’t new and that the vaccines have proven benefits. Various posts made unfounded claims, stating or implying that people should not have received the vaccines , that the risks outweigh the benefits or that the  risk of the rare side effects is greater than was reported in the study.

“Hundreds of millions of people were used as lab rats and now the truth that WE ALL ALREADY KNEW can no longer be denied,” said one popular  post , referring to the vaccines as “experimental” and “UNTESTED.” The post shared a screenshot of the headline of a New York Post  article  about the new study, which read, “COVID vaccines linked to slight increases in heart, brain, blood disorders: study.”

“This thing was forced on people who faced almost no risk from Covid,” said another widely read post . “It is completely unacceptable.” The post shared statistics from the paper without making it clear that serious health problems after vaccination were rare and that risk varied by vaccine type and dose.

The Vaccine study confirmed that the Moderna and Pfizer/BioNTech vaccines are linked in rare cases to myocarditis and pericarditis, conditions involving inflammation of the heart muscle and lining. The rate of myocarditis was most elevated after the second dose of the Moderna vaccine. Myocarditis risk — which is greatest in men in their late teens and early twenties — was  identified via vaccine safety monitoring and first reported in 2021. Based on the current evidence, the  CDC says, the benefit of vaccination outweighs the risk of these conditions, which improve for most people after medical treatment and rest.

The study confirmed neurological and blood clotting conditions associated with the AstraZeneca vaccine. In the U.S., these  problems  were  linked  to the Johnson & Johnson vaccine, contributing to this vaccine no longer being recommended or available.

The study also identified a new possible safety signal indicating a potential link between the first dose of the Moderna and AstraZeneca vaccines and rare neurological conditions. This included an association between the first doses of the vaccines and acute disseminated encephalomyelitis, or ADEM, an autoimmune condition that causes inflammation of the brain and spinal cord.

Hviid emphasized that the researchers only saw these neurological events after first doses of the two vaccines. “We did not see these signals following further doses of these two Covid-19 vaccines, nor did we see them after any dose of the Pfizer/BioNTech vaccine which has been more widely used,” he said.

“We are also talking about very rare events,” Hviid continued. “As an example, the association between the first dose of Moderna and acute inflammation of the brain and spine would, if causal, correspond to 1 case per 1.75 million vaccinated. It is only due to the sheer scale of our study, that we have been able to identify this minute potential risk.”

Study Bolsters the Evidence Serious COVID-19 Vaccine Side Effects Are Rare

The Vaccine  study  drew on national or regional health records from eight countries with institutions participating in the  Global Vaccine Data Network , an international group that studies vaccine safety. The researchers analyzed health outcomes after around 184 million doses of the Pfizer/BioNTech vaccine, 36 million doses of the Moderna vaccine and 23 million doses of the AstraZeneca vaccine. 

The researchers focused on 13 health problems that either had a known association with vaccination or for which there was some rationale to investigate whether there was an association. To determine whether the health problems were associated with vaccination, they compared the expected rates of the health problems — or the number of health events that should occur based on background rates in the regions studied — with the number of events they observed in the 42 days after vaccination.

“This study confirms the primary already detected and validated side effects established by previous literature,”  Jeffrey S. Morris , director of the division of biostatistics at the University of Pennsylvania’s Perelman School of Medicine, told us via email, referring to the rare heart conditions associated with the Moderna and Pfizer/BioNTech vaccines, as well as the rare conditions associated with the AstraZeneca and Johnson & Johnson vaccines. 

Morris said that findings on ADEM — the rare autoimmune neurological condition linked to first doses of the Moderna and AstraZeneca vaccines — “might be a new safety signal.” 

ADEM  involves  inflammation to the brain and spinal cord, arising most often in children following an infectious illness. It has a  sudden onset  and typically eventually improves, with a full recovery in many, although not all, cases.

After the first dose of the Moderna vaccine, researchers observed seven ADEM cases, when they expected two. As we’ve said, Hviid calculated the rate of this side effect — if ultimately shown to be related to vaccination — to be 1 in 1.75 million following the first dose of the Moderna vaccine. 

The data show “this was indeed an EXTREMELY rare adverse event,” Morris said, referring to ADEM. “It is understandable at this incidence rate why it may not have been detected before now, and why a study with 99 million participants like this is important to find even the most rare serious adverse events that are potential minority harm risks of these vaccines.”

The authors of the study wrote that more research is needed into ADEM following COVID-19 vaccination, saying that “the number of cases of this rare event were small and the confidence interval wide, so results should be interpreted with caution and confirmed in future studies.” The authors also wrote that neurological  events  have been found to occur at a much higher rate after COVID-19 than after COVID-19 vaccination.

The study means that “early warning systems are solid,” said  Marc Veldhoen , an immunologist at the Instituto de Medicina Molecular João Lobo Antunes in Portugal, in a  post  on X, formerly known as Twitter. “To avoid any adverse reaction is not possible, but, identifying those at higher risk may be possible.”

Identifying those at greater risk of side effects can help guide decisions on which vaccines to recommend and what problems doctors should watch for in their patients.

Editor’s note: SciCheck’s articles providing accurate health information and correcting health misinformation are made possible by a grant from the Robert Wood Johnson Foundation. The foundation has no control over FactCheck.org’s editorial decisions, and the views expressed in our articles do not necessarily reflect the views of the foundation.

“ How do we know vaccines are safe? ” FactCheck.org. Updated 8 Jul 2021.

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TheBlaze. “ Blood clots, neurological disorders, and swollen hearts: Multinational study on COVID vaccines paints a damning picture .” Facebook. 20 Feb 2024.

Dr. Anthony G. Jay (@anthonygjay). “ I post a lot of vids but rarely PLUG them WATCH my YouTube vid on this – it’s 6 minutes – before it gets taken down 🤐 .” Instagram. 20 Feb 2024.

bikinibottom_fish 🐟 (@bikinibottom_fish). “ Global Study Links COVID-19 Vaccines to Heart and Brain Issues! ” Instagram. 20 Feb 2024.

PatrioticBabe 🇺🇸 (@babedoesthenews). “ ❗️ .” Instagram. 20 Feb 2024.

RASPY RAWLS (@raspy_rawls2). “ … We told yall not to take that shyt but hey wat dew we know 🤷🏾‍♂️ …  .” Instagram. 20 Feb 2024.

Jaimee Michell (@thegaywhostrayed). “ I want to know if you think Trump holds any blame, and if not, why not? COMMENT your thoughts BELOW! ” Instagram. 20 Feb 2024.

Liberty Counsel (@libertycounsel). “ …  “Based on ‘conservative assumptions,’ the estimated harms of the COVID-19 mRNA vaccines ‘greatly outweigh the rewards,’ the article stated, noting that ‘for every life saved, there were nearly 14 times more deaths caused by the modified mRNA injections.’” … ” Instagram. 20 Feb 2024.

Shemeka Michelle (@ theshemekamichelle ). “ Remember when they called them “rare” breakthrough cases? Yeah, me too. #slight .” Instagram. 20 Feb 2024.

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• Covid-19: Two rare...

Covid-19: Two rare vaccine side effects detected in large global study

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• Jacqui Wise

The largest vaccine safety study to date has identified two new, but very rare, side effects associated with covid-19 vaccines—transverse myelitis and acute disseminated encephalomyelitis.

The Global Vaccine Data Network cohort study included 99 million vaccinated people from 10 sites across eight countries. Researchers compared the observed with expected rate for 13 neurological, blood, and heart related medical conditions.

The study, published in Vaccine , confirmed previously identified rare safety signals for myocarditis and pericarditis after a mRNA vaccine (Pfizer and Moderna) and Guillain-Barré syndrome and cerebral venous sinus thrombosis (CVST) after viral vector vaccines (AstraZeneca). 1

There was a statistically significant increase in Guillain-Barré syndrome within 42 days after the first dose of the AstraZeneca vaccine—76 events were expected and 190 events were observed (observed to expected ratio 2.49; 95% confidence interval 2.15 to 2.87). A statistically significant increased risk of CVST was also observed following the first dose of the AstraZeneca vaccine (OE ratio 3.23; 95% CI 2.51 to 4.09).

The study also confirmed significantly higher risks of myocarditis following the first, second, and third doses of the Pfizer and Moderna vaccines as well as pericarditis after the first and fourth dose of Moderna vaccine, and third dose of AstraZeneca vaccine in the 42 days following vaccination.

As well as these known risks the researchers also identified a possible safety signal for acute disseminated encephalomyelitis (AEDM) and transverse myelitis with both viral vector and mRNA vaccines.

This was then further investigated by a second study, also published in Vaccine , which analysed a separate dataset for 6.7 million people in Australia. 2

This study found an increased risk of ADEM (all dose relative incidence 3.74; 95% CI 1.02 to 13.70) and transverse myelitis (dose 1 RI 2.49; 95% CI 1.07 to 5.79) associated with the AstraZeneca vaccine. No associations were observed between mRNA covid-19 vaccines and either side effect.

The researchers said the findings translate to “an extremely small absolute risk” of acute disseminated encephalomyelitis (0.78 per million vaccine doses) and of transverse myelitis (1.82 per million vaccine doses). “Any potential risk of acute disseminated encephalomyelitis or transverse myelitis should be weighed against the well established protective benefits of vaccination against covid-19 and its complications,” they wrote.

“The size of the population in this study increased the possibility of identifying rare potential vaccine safety signals,” said lead author Kristýna Faksová of the department of epidemiology research, Statens Serum Institut, Copenhagen, Denmark. “Single sites or regions are unlikely to have a large enough population to detect very rare signals.”

The Global Covid Vaccine Safety Project is funded by the US Centers for Disease Control and Prevention to allow the comparison of the safety of vaccines across diverse global populations.

• ↵ Faksova K, Walsh D, Jiang Y, et al. Covid-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals. Vaccine 2024 Feb 12:S0264-410X(24)00127-0 . doi: 10.1016/j.vaccine.2024.01.100
• ↵ Morgan H, Clothier H, Kattan G, et al. Acute disseminated encephalomyelitis and transverse myelitis following covid-19 vaccination—a self controlled case series analysis. Vaccine 2024 Feb 12:S0264-410X(24)00126-9 .

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A review of adverse effects of COVID-19 vaccines

Hisham ahmed mushtaq, anwar khedr, thoyaja koritala, brian n bartlett, nitesh k jain, syed anjum khan.

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Corresponding author: Syed Anjum Khan, E-mail: [email protected]

Corresponding author.

Received 2022 Dec 10; Accepted 2022 Feb 7; Collection date 2022.

The COVID-19 pandemic has led to unanticipated pressures on all aspects of human life. Multiple approaches to eliciting protective immunity must be rapidly evaluated. Numerous efforts have been made to develop an effective vaccine for this novel coronavirus, resulting in a race for vaccine development. To combat COVID-19, all nations must focus their efforts on widespread vaccination with an effective and safe vaccine. Globally, concerns about potential long-term adverse effects of vaccines have led to some apprehension about vaccine use. A vaccine’s adverse effect has an integral role in the public’s confidence and vaccine uptake. This article reviews the current primary literature regarding adverse effects associated with different COVID-19 vaccines in use worldwide.

Keywords: adverse effects, adverse events, complications, COVID-19, vaccine

As of January 14, 2022, the World Health Organization (WHO) has confirmed about 318,648,834 cases of COVID-19 worldwide, including 5,518,343 fatalities [ 1 ]. The COVID-19 pandemic has resulted in a global economic disruption. To restore normalcy and enable economic growth, vaccines are the best option. The first COVID-19 vaccine introduced in December 2020 has become a milestone in the fight against this pandemic. On December 2, 2020, using an Emergency Use Authorization (EUA), the UK became the first country to approve Pfizer-BioNTech’s COVID-19 vaccine, BNT162 [ 2 ]. As of December 31, 2020, the WHO approved BNT162 for emergency use, making its global production and supply more efficient [ 3 ]. Different vaccine candidates for COVID-19 have been approved using similar EUA processes, and the list continues to grow.

A historic vaccination campaign is taking place in the US currently. In 1 week, 1.12 million doses were administered daily, on average. More than 523 million doses have been given in the US to date ( Figure 1 ) [ 4 , 5 ]. As of January 14, 2022, 194 vaccines are in preclinical development, and 139 are in clinical trials [ 6 ].

COVID-19 Vaccines Administered in the US by Manufacturer [ 5 ].

Vaccine uptake must be accelerated in the coming months to continue to decrease infection rates [ 7 ]. However, some people question whether the speed at which a vaccine is developed will compromise its efficiency and safety. This, in turn, may lead to vaccine hesitancy, which further inhibits attaining the goal of having 70% of the population fully vaccinated, after which herd immunity can effectively be achieved [ 8 ]. Therefore, it is crucial to establish the safety of the vaccines in these circumstances to perhaps promote wider vaccine acceptance among hesitant people. Adverse effects, however, are associated with every vaccination [ 9 ]. The purpose of this article is to review the current primary literature regarding adverse affects associated with the different COVID-19 vaccines. Our aim is to provide insights into the safety of the vaccines to help address misinformation and vaccine hesitancy. We discuss the adverse effects of the most common vaccines, which were chosen based on the number of countries they are approved in.

This article is intended to be a narrative review. Searches were conducted in PubMed and Google Scholar to identify related literature from 2020 to 2021. Keywords such as “adverse effects,” “adverse events,” “complications,” “COVID-19,” and “vaccine,” were searched individually or in combination to yield relevant information. The results were reviewed for relevance to the topic, and the articles were screened by 2 authors. We had no language restrictions because of the relatively few articles on the topic. Duplicated studies and studies providing insufficient and irrelevant information were excluded.

MRNA VACCINES

Pfizer-biontech.

Pfizer-BioNTech’s BNT162 vaccine is a lipid nanoparticle-derived, nucleoside-modified mRNA vaccine that encodes the SARS-CoV-2 glycoprotein spike [ 10 ]. The UK was the first nation to approve BNT162 on December 2, 2020 [ 2 ]. A first EUA for BNT162 was issued by the US Food and Drug Administration (FDA) on December 11, 2020 [ 11 ]. BNT162 was later approved by Canada and Mexico via their respective EUAs. The WHO approved the first vaccine candidate, BNT162, on December 31, 2020, for emergency use, therefore facilitating easy production and distribution globally [ 3 ]. A total of 232.52 million doses of the Pfizer-BioNTech vaccine have been given in the US through October 7, 2021 [ 12 ].

mRNA-1273 from Moderna is a lipid-encapsulated mRNA vaccine that encodes the SARS-CoV-2 prefusion-stabilized spike protein [ 13 ]. The FDA issued an EUA for mRNA-1273 on December 18, 2020 [ 11 ]. It was the second COVID-19 vaccine in the US to be authorized under an EUA [ 14 ]. As of October 7, 2021, 152.51 million doses of Moderna vaccine have been given in the US [ 12 ].

Considerations with mRNA vaccines

For the 2 mRNA vaccines, the second dose was associated with more adverse effects than the first dose [ 15 ]. A higher rate of systemic events was reported by younger vaccine recipients (aged 16–55 years) than those older than 55 years, which may be due to a more robust immunogenic response in younger persons [ 15 ].

Evaluation of the vaccines vs placebo (normal saline) showed a higher incidence of mild local adverse effects such as pain, heat, swelling, and redness [ 15 ]. The vaccines were also associated with other systemic adverse effects such as fever, fatigue, arthralgias, myalgias, and headache. These adverse effects usually developed within 1 to 2 days of vaccination [ 15 ].

In initial trials, the localized symptoms were mild to moderate in severity and lasted 1 to 2 days. Moderate to severe systemic symptoms, such as headache, myalgia, arthralgia, and fatigue, also lasted 1 to 2 days [ 15 ]. More local reactions were seen among the vaccine group than the placebo group. The most common localized symptom was pain at the injection site, which was seen within 1 week of vaccination [ 15 ]. Anaphylaxis and edema of the labial, facial, and glossal areas were among the adverse events noted [ 16 ].

ADENOVIRAL VACCINES

Oxford/astrazeneca chadox1 ncov-19 vaccine (azd1222).

The SARS-CoV-2 structural surface spike protein gene is integrated into the ChAdOx1 nCoV-19 vaccine (AZD1222; trade name Vaxzevria) from Oxford/AstraZeneca, which is made from replication-deficient chimpanzee adenovirus ChAdOx1 [ 17 ]. Efficacy and safety results for AZD1222 have been documented in 4 randomized clinical trials in the UK, South Africa, and Brazil [ 17 ]. Overall, the vaccine was safe across all 4 studies, and serious adverse events were evenly distributed among all study groups. A total of 168 serious adverse events were reported among 79 recipients of AZD1222 and 89 recipients of saline control [ 17 ]. One case of transverse myelitis was reported 14 days after the second dose of AZD1222; this was viewed as possibly related to vaccination, and a diagnosis of an idiopathic, short-segment, spinal cord demyelination was made. In South Africa, 1 patient had a fever higher than 40°C 2 days after vaccination, but the patient recovered quickly [ 17 ]. In another study, laboratory tests in 11 patients in Austria and Germany indicated either thrombocytopenia or thrombosis after being vaccinated with AZD1222 [ 18 ]. The Supplemental Figure shows the number of individual events by reaction group identified in the European database of suspected adverse drug reaction reports (EudraVigilance) for AZD1222 (up to January 15, 2022) [ 19 ].

Johnson & Johnson (Janssen) Ad26.COV2.S

The Ad26.COV2.S vaccine from Johnson & Johnson (Janssen) was the third COVID-19 vaccine approved to be used in the US. Ad.26.COV2.S employs a human adenoviral type 26 vector platform [ 20 ]. The first 2 approved mRNA vaccines require 2 doses, whereas the Janssen vaccine is given as a single dose intramuscularly. Ad.26.COV2.S was granted an EUA by the FDA on Feb 27, 2021 [ 14 ]. Low- and middle-income countries prefer adenoviral vaccines because they do not require high-level cold-chain storage, and Ad26.COV2.S requires only 1 dose [ 20 ].

After 6 recipients were diagnosed with cerebral venous sinus thrombosis and thrombocytopenia, the FDA and the Centers for Disease Control and Prevention (CDC) recommended a pause in the administration of Janssen vaccines [ 21 ]. In Europe, reports of similar thrombotic events have been observed primarily among women younger than 60 years after receiving the AstraZeneca AZD1222 vaccine [ 20 ].

Sputnik V (Gam-COVID-Vac) is a 2-part adenoviral vaccine against SARS-CoV-2. Specifically, it contains the DNA for the spike protein encoded by SARS-CoV-2 that the virus uses to infect human cells. An immune response is triggered to the spike protein [ 22 ]. This vaccine consists of 2 adenoviral vectors (rAd26 and rAd5) administered in separate doses, 21 days apart. [ 23 ] The use of recombinant adenovirus is similar to the Oxford AstraZeneca and the Janssen vaccines [ 17 , 24 ].

The Gamaleya National Center of Epidemiology and Microbiology in Moscow was already devising prototypes of Sputnik V when the WHO declared COVID-19 a pandemic [ 25 ]. In September 2020, researchers published results from phases I and II of an open, nonrandomized trial of 76 participants [ 26 ]. All participants were reported to have developed antibodies against SARS-CoV-2. Pain at the injection site (44 [58%]), asthenia (21 [28%]), headache (32 [42%]), hyperthermia (38 [50%]), and muscle pain (18 [24%]) were among the most common adverse events. Serious adverse events were not observed [ 26 ]. The rapidity and lack of transparency in the development of the Sputnik V vaccine have been criticized, however [ 27 ].

The phase III interim report included results for more than 20,000 participants. The vaccine was not directly linked to any serious adverse events. However, 45 participants who were given the vaccine and 23 who were given the placebo experienced serious adverse effects that were not related to the vaccine [ 26 ].

SURVEILLANCE PROGRAMS

To confirm vaccine safety, an objective analysis of adverse effects and potential adverse reactions is required. To this effect, several surveillance programs are used. The Vaccine Adverse Event Reporting System (VAERS), created by the CDC and FDA, monitors adverse reactions after vaccination ( Figure 2 ) [ 28 , 29 ]. Reports can be submitted by vaccine manufacturers, health care providers, and the general public. VAERS requires reporting of various adverse events by health care providers, including deaths, as part of the European Union Agreements on COVID-19 vaccines [ 28 ].

Vaccine Adverse Events According to the Vaccine Adverse Event Reporting System [ 29 ]. Events reported through October 7, 2021.

VAERS database entries do not indicate a causal relationship between vaccination and the cases. In addition, the VAERS database is based on passive surveillance and therefore could be biased or contain errors resulting from reporting bias. Because of the large number of vaccines administered and the prevalence of serious adverse events in the population, some cases of these conditions may occur by chance during the postvaccination period, unrelated to the vaccines themselves [ 30 ]. Constitutional symptoms reported to VAERS as of January 7, 2022, are shown in Table 1 [ 31 , 32 ].

Constitutional Symptoms Reported to the Vaccine Adverse Event. Reporting System as of January 2022.

The v-safe program is a system of surveillance using text messages to collect information regarding vaccine adverse effects. In v-safe, vaccine recipients are consistently prompted to complete short medical surveys, including an inquiry about the injection site and systemic reactions and health effects. When enrollees seek medical care, the v-safe call center notifies them and encourages them to fill out a VAERS report [ 28 ].

SPECIFIC ADVERSE EVENTS

Recently, several reports of thrombocytopenia with thrombosis, most notably cerebral venous sinus thrombosis or cerebral venous thrombosis (CVT) within 28 days of vaccination, have been associated with Ad26.COV2.S (Janssen) and AZD1222 (AstraZeneca) ( Table 2 ), both of which use the adenovirus-vector platform [ 19 , 33 ]. Reports of thrombosis could have implications for vaccine uptake all over the world. Consequently, many nations have altered their vaccination guidelines. AZD1222 was made available only to adults older than 40 years in the UK, older than 55 years in Canada, and older than 60 years in Germany [ 33 – 35 ]. As a result of 6 reports of CVT, the FDA and CDC recommended a pause in the administration of Ad26.COV2.S vaccine in the US on April 13, 2021 [ 21 ].

Cases of Cerebral Venous Thrombosis and Cerebral Venous Sinus Thrombosis by Age and Sex a .

Cerebral venous thrombosis and cerebral venous sinus thrombosis cases reported to EudraVigilance for COVID-19 vaccine AZD1222 (AstraZeneca) up to January 15, 2022.

New-onset severe headache is an important symptom of CVT and occurs in up to 67% of persons within the first few days after COVID-19 immunization [ 36 ]. It is critical for health care providers to diagnose CVT in vaccinated patients and to evaluate and treat patients with suspicion of immune-mediated thrombocytopenia with thrombosis resulting from vaccination. A CVT event occurs when the smaller draining cortical veins or the cerebral venous sinus system are completely or partially occluded [ 37 ]. It is more likely to occur in young adults and is 3 times as common among women than men [ 38 ].

Antibodies to platelet factor 4 (PF4) were detected in several patients who had CVT events after vaccination with Ad26.COV2.S and AZD1222 vaccines, which mimicked autoimmune heparin-induced thrombocytopenia [ 39 ]. Antibody complexes involving PF4 are formed which bind the Fc gamma receptor of platelets, form crosslinks, and activate the platelets [ 18 ]. Similar to heparin-induced thrombocytopenia, when platelets are consumed, thrombocytopenia is precipitated, and when monocytes and platelets are activated, thrombin production increases, which leads to thrombosis. In addition, an increase in D-dimer levels is seen, and eventually, it leads to disseminated intravascular coagulation [ 18 ]. The reason for adenoviral vector vaccines being associated with PF4 antibody production and thrombosis is unknown, but animal trials have shown that adenoviral vaccines can be biodistributed in the brain. Therefore, the presence of spike protein in the cerebral tissues can trigger an autoimmune reaction and eventual thrombosis [ 40 ].

The development of CVT is 41 times more likely in patients with COVID-19 than those without COVID-19, according to analyzed TriNetX data [ 41 ]. Thus, COVID-19 vaccination provides an overall benefit. In the US, on April 27, 2021, authorities decided to resume the use of the Ad26. COV2.S vaccine in all adults older than 18 years [ 42 ]. However, the CDC included a warning for women younger than 50 years on the risks of thrombosis associated with this vaccine [ 43 ].

Guillain-Barré syndrome

In developed countries, Guillain-Barré syndrome (GBS) is one of the leading causes of acute flaccid paralysis, characterized by autonomic dysfunction, sensory abnormalities, and varying degrees of weakness. Although the specific pathophysiology is not known, this disorder is believed to result from an autoimmune response [ 44 ].

mRNA from the approved mRNA vaccines gains access into the human cell and directs it to synthesize a copy of the spike protein found on the virus’s surface and produce antibodies against it. These antibodies become primed to inactivate the virus before it can cause the disease. Sometimes, however, a patient’s immune response can trigger the synthesis of antibodies against myelin, causing GBS [ 45 ].

A case of GBS was seen in the UK in a 62-yearold woman who had paraesthesias and weakness of the lower limbs 11 days after her initial dose of AZD1222 vaccine [ 46 ]. Another 82-year-old woman received her initial dose of the BNT162 vaccine 2 weeks before the diagnosis of GBS [ 45 ]. Approximately 17 cases of GBS develop per million people worldwide each year. With previous 1976 Swine flu and 2009 H1N1 vaccines, studies showed no increase in cases of GBS after vaccination [ 47 ]. To date, there is no substantial evidence that any of the COVID-19 vaccines cause GBS. Furthermore, no association was found between infection with COVID-19 and GBS. As a result, there is a low probability that GBS incidence will increase after COVID-19 vaccination [ 48 ]. COVID-19 poses a much greater risk of mortality and morbidity for adults than GBS does [ 49 ].

Acute transverse myelitis

Acute transverse myelitis is an uncommon neurologic condition affecting people aged 35 to 40 years at an incidence of 1.34 to 4.6 cases/million adults per year [ 50 ]. Of the reported adverse events after immunization recorded in the VAERS, 341 were neurologic events, 122 of which were cases of transverse myelitis [ 31 ]. Interleukin (IL)-17 and IL-6 appear to be involved in the pathogenesis of transverse myelitis. In myelitis, cerebrospinal fluid analysis findings show increased IL-6 levels [ 51 ]. By regulating cytokines, IL-17 stimulates astrocytes to produce IL-6, which forms nitric oxide metabolites and causes CNS damage [ 51 ].

Three cases of transverse myelitis were reported in the trial phase of the recombinant AZD1222 vaccine. Among these 3, 1 case had a background of multiple sclerosis; another was initially termed a potentially related case, but this was later ruled out by experts [ 17 ]. The presence of chimpanzee adenovirus antigen in AZD1222 may instigate immune responses targeting the spinal cord, which may in turn result in acute transverse myelitis [ 52 ]. COVID-19 - associated acute transverse myelitis should be investigated to identify the responsible antigen and explore immunopathogenesis.

Myocarditis and pericarditis

Myocarditis is an inflammation of the myocardial tissue without signs of ischemia and has various causes and diverse patterns [ 53 ]. In a study involving 7 patients with myocarditis between February 1 and April 30, 2021, 4 were diagnosed within 5 days after receiving COVID-19 vaccination. These 4 patients, who had received the second dose of an mRNA vaccine, reported chest pain and had increased biomarker levels suggestive of myocardial tissue injury. Cardiac magnetic resonance imaging results showed characteristics of myocarditis [ 54 ].

According to the CDC, more than 10,000 reports of myocarditis were reported to the VAERS after COVID-19 vaccination (Pfizer-BioNTech and Moderna) in the US ( Table 3 ) [ 29 ]. These reports, however, are infrequent compared with the hundreds of millions of vaccine doses that were administered without adverse effects. The majority of the confirmed cases have been in teenagers and young adults 16 years or older and were often seen after receiving the second dose of the vaccine [ 55 ]. In a study of 200,287 persons, medical records from 40 hospitals in California, Montana, Los Angeles County, Oregon, and Washington were reviewed to identify cases of myocarditis and pericarditis after vaccination [ 56 ]. Myocarditis developed in 20 persons and pericarditis in 37. The incidence of myocarditis was highest among younger patients, generally after the second dose. However, older patients had development of pericarditis after the first or second dose [ 56 ]. In another study, vaccination for COVID-19 led to myocarditis in 23 male patients, 22 of whom were healthy members of the military [ 57 ]. In the majority of the patients, the diagnosis was made at least 4 days after the second dose of vaccination [ 57 ]. The clinical course and presentation suggest an association with vaccination-induced inflammation.

Myopericarditis Events and Related Deaths Reported to the Vaccine Adverse Event Reporting System as of January 7, 2022.

Cutaneous reactions

In a study from December 2020 to February 2021, 414 cutaneous symptoms were noted after administration of an mRNA vaccine [ 58 ]. Injection-site reactions, with delayed local reactions and urticarial and morbilliform eruptions, were the most commonly observed findings. Among recipients with first-dose reactions, 43% also had recurrences after their second dose [ 58 ]. Other reactions less commonly reported were pernio/chilblain, pityriasis rosea-like reactions, zoster, cosmetic filler reactions, and herpes simplex exacerbations. Some dermatologic symptoms, like pernio/chilblain, imitated COVID-19 symptoms. None of the patients reported serious adverse effects after receiving either of the doses [ 58 ]. As a result, researchers concluded that COVID-19 vaccination generally causes only mild and self-limiting reactions, and people should not be discouraged from the vaccination because of them [ 58 ].

Glomerular disease

Since mass-vaccination campaigns began in January 2021, the incidence of vaccine-associated glomerular disease has increased [ 59 ]. Symptoms of recurrent glomerular diseases or new glomerular diseases have appeared, especially after administration of the mRNA vaccines. The pathogenesis behind vaccine-associated glomerular disorders is not clearly understood. However, an immunogenic response to vaccines has been noted as a possible cause [ 60 ]. Minimal change disease, anti-glomerular basement membrane disease, membranous glomerular disease, and immunoglobulin A nephropathy are some of the glomerular lesions observed after vaccination [ 60 ]. Some case reports have described patients with gross hematuria after vaccination who were later found to have immunoglobulin A nephropathy. The majority of vaccine-related cases were typically seen within 1 to 3 weeks after vaccination [ 59 ]. Management of the glomerular disease must be on a case-by-case basis depending on the severity and remission status, because the benefits of vaccination outweigh the rare risk of glomerular disease.

CONCLUSIONS

COVID-19 is a global health concern that has spread worldwide [ 61 ] and has dramatically changed global sociopolitical, economic, and cultural aspects of humanity [ 62 ]. COVID-19 vaccines became more and more critical due to the limited prevention and treatment options available [ 63 ]. To end the pandemic crisis, the development of affordable, effective, safe, and transportable vaccines has become necessary. Some risks are associated with COVID-19 vaccinations, but no vaccination is entirely safe. Generally, short-term adverse effects of the COVID-19 vaccines present with mild symptoms. The most common symptoms are localized pain and swelling at the injection site, fever, headache, myalgia, and chills. Cases of thrombosis, notably CVT, are mostly seen with the adenoviral vector vaccines. Adverse effects such as myocarditis, glomerular diseases, and cutaneous eruptions are seen with the mRNA vaccines. The majority of vaccination reactions peak within the first 6 weeks after receiving the vaccine, but tracking over a longer time frame may provide insight into any future adverse reactions and rule out reactions that are falsely attributed to vaccinations. It is essential to identify the underlying immunologic and nonimmunologic mechanisms of adverse events so that appropriate policies are adopted, keeping safety in mind.

Supplementary Data

Acknowledgments.

The Scientific Publications staff at Mayo Clinic provided editorial consultation, proofreading, and administrative and clerical support.

Conflict of interest

None to declare.

None to decleare.

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What are the benefits of getting a covid-19 vaccine.

Staying up to date with a COVID-19 vaccine can:

• Help prevent serious illness and death due to COVID-19 for both children and adults.
• Help prevent you from needing to go to the hospital due to COVID-19 .
• Be a less risky way to protect yourself compared to getting sick with the virus that causes COVID-19.
• Lower long-term risk for cardiovascular complications after COVID-19.

Factors that can affect how well you're protected after a vaccine can include your age, if you've had COVID-19 before or if you have medical conditions such as cancer.

How well a COVID-19 vaccine protects you also depends on timing, such as when you got the shot. And your level of protection depends on how the virus that causes COVID-19 changes and what variants the vaccine protects against.

Talk to your healthcare team about how you can stay up to date with COVID-19 vaccines.

Should I get the COVID-19 vaccine even if I've already had COVID-19?

Yes. Catching the virus that causes COVID-19 or getting a COVID-19 vaccination gives you protection, also called immunity, from the virus. But over time, that protection seems to fade. The COVID-19 vaccine can boost your body's protection.

Also, the virus that causes COVID-19 can change, also called mutate. Vaccination with the most up-to-date variant that is spreading or expected to spread helps keep you from getting sick again.

Researchers continue to study what happens when someone has COVID-19 a second time. Later infections are generally milder than the first infection. But severe illness can still happen. Serious illness is more likely among people older than age 65, people with more than four medical conditions and people with weakened immune systems.

Safety and side effects of COVID-19 vaccines

What covid-19 vaccines have been authorized or approved.

The COVID-19 vaccines available in the United States are:

• Pfizer-BioNTech COVID-19 vaccine 2024-2025 formula, available for people age 6 months and older.
• Moderna COVID-19 vaccine 2024-2025 formula, available for people age 6 months and older.
• Novavax COVID-19 vaccine 2024-2025 formula, available for people age 12 years and older.

These vaccines have U.S. Food and Drug Administration (FDA) emergency use authorization or approval.

In June 2024, the FDA recommended COVID-19 vaccine updates to target a strain of the COVID-19 virus called JN.1. But JN.1 soon began to fade from the community. Strains that evolved from it began to spread at higher levels. As the virus continued to change, the FDA updated its guidance and asked vaccine makers to focus on a JN.1 strain subtype called KP.2.

The Pfizer-BioNTech and Moderna COVID-19 vaccines for 2024-2025 focus on building protection against the KP.2 virus strain. The Novavax COVID-19 vaccine, adjuvanted 2024-2025 formula will focus on the JN.1 strain.

In December 2020, the Pfizer-BioNTech COVID-19 vaccine two-dose series was found to be both safe and effective in preventing COVID-19 infection in people age 18 and older. This data helped predict how well the vaccines would work for younger people. The effectiveness varied by age. Since 2020, the vaccine has been updated yearly to better protect against the strains of COVID-19 spreading in the community. The currently approved vaccine is Pfizer-BioNTech COVID-19 vaccine 2024-2025 formula.

The Pfizer-BioNTech vaccine is approved under the name Comirnaty for people age 12 and older. The FDA authorized the vaccine for people age 6 months to 11 years. The number of shots in this vaccination series varies based on a person's age and COVID-19 vaccination history.

In December 2020, the Moderna COVID-19 vaccine was found to be both safe and effective in preventing infection and serious illness among people age 18 or older. The vaccine's ability to protect younger people was predicted based on that clinical trial data. Since 2020, the vaccine has been updated yearly to better protect against the changing strains of COVID-19. The currently approved vaccine is Moderna COVID-19 vaccine 2024-2025 formula.

The FDA approved the vaccine under the name Spikevax for people age 12 and older. The FDA authorized use of the vaccine in people age 6 months to 11 years. The number of shots needed varies based on a person's age and COVID-19 vaccination history.

In July 2022, this vaccine was found to be safe and effective and became available under an emergency use authorization for people age 18 and older. In August 2022, the FDA authorized the vaccine for people age 12 and older. Since then, the vaccine has been updated yearly to better protect against the changing strains of COVID-19. The currently approved vaccine is Novavax COVID-19 vaccine, adjuvanted 2024-2025 formula.

How do the COVID-19 vaccines work?

COVID-19 vaccines help the body get ready to clear out infection with the virus that causes COVID-19.

Both the Pfizer-BioNTech and the Moderna COVID-19 vaccines use genetically engineered messenger RNA (mRNA). The mRNA in the vaccine tells your cells how to make a harmless piece of virus that causes COVID-19.

After you get an mRNA COVID-19 vaccine, your muscle cells begin making the protein pieces and displaying them on cell surfaces. The immune system recognizes the protein and begins building an immune response and making antibodies. After delivering instructions, the mRNA is immediately broken down. It never enters the nucleus of your cells, where your DNA is kept.

The Novavax COVID-19 adjuvanted vaccine is a protein subunit vaccine. These vaccines include only protein pieces of a virus that cause your immune system to react the most. The Novavax COVID-19 vaccine also has an ingredient called an adjuvant that helps raise your immune system response.

With a protein subunit vaccine, the body reacts to the proteins and creates antibodies and defensive white blood cells. If you later become infected with the COVID-19 virus, the antibodies will fight the virus. Protein subunit COVID-19 vaccines don't use any live virus and can't cause you to become infected with the COVID-19 virus. The protein pieces also don't enter the nucleus of your cells, where your DNA is kept.

Can a COVID-19 vaccine give you COVID-19?

No. The COVID-19 vaccines available in the U.S. don't use the live virus that causes COVID-19. Because of this, the COVID-19 vaccines can't cause you to become sick with COVID-19.

It can take a few weeks for your body to build immunity after getting a COVID-19 vaccination. As a result, it's possible that you could become infected with the virus that causes COVID-19 just before or after being vaccinated.

What are the possible general side effects of a COVID-19 vaccine?

Some people have no side effects from the COVID-19 vaccine. For those who get them, most side effects go away in a few days.

A COVID-19 vaccine can cause mild side effects after the first or second dose. Pain and swelling where people got the shot is a common side effect. That area also may look reddish on white skin. Other side effects include:

• Fever or chills.
• Muscle pain or joint pain.
• Tiredness, called fatigue.
• Upset stomach or vomiting.
• Swollen lymph nodes.

For younger children up to age 4, symptoms may include crying or fussiness, sleepiness, loss of appetite, or, less often, a fever.

In rare cases, getting a COVID-19 vaccine can cause an allergic reaction. Symptoms of a life-threatening allergic reaction can include:

• Breathing problems.
• Fast heartbeat, dizziness or weakness.
• Swelling in the throat.

If you or a person you're caring for has any life-threatening symptoms, get emergency care.

Less serious allergic reactions include a general rash other than where you got the vaccine, or swelling of the lips, face or skin other than where you got the shot. Contact your healthcare professional if you have any of these symptoms.

You may be asked to stay where you got the vaccine for about 15 minutes after the shot. This allows the healthcare team to help you if you have an allergic reaction. The healthcare team may ask you to wait for longer if you had an allergic reaction from a previous shot that wasn't serious.

Contact a healthcare professional if the area where you got the shot gets worse after 24 hours. And if you're worried about any side effects, contact your healthcare team.

Are there any long-term side effects of the COVID-19 vaccines?

The vaccines that help protect against COVID-19 are safe and effective. Clinical trials tested the vaccines to make sure of those facts. Healthcare professionals, researchers and health agencies continue to watch for rare side effects, even after hundreds of millions of doses have been given in the United States.

Side effects that don't go away after a few days are thought of as long term. Vaccines rarely cause any long-term side effects.

If you're concerned about side effects, safety data on COVID-19 vaccines is reported to a national program called the Vaccine Adverse Event Reporting System in the U.S. This data is available to the public. The U.S. Centers for Disease Control and Protection (CDC) also has created v-safe, a smartphone-based tool that allows users to report COVID-19 vaccine side effects.

If you have other questions or concerns about your symptoms, talk to your healthcare professional.

Can COVID-19 vaccines affect the heart?

In some people, COVID-19 vaccines can lead to heart complications called myocarditis and pericarditis. Myocarditis is the swelling, also called inflammation, of the heart muscle. Pericarditis is the swelling, also called inflammation, of the lining outside the heart.

Symptoms to watch for include:

• Chest pain.
• Shortness of breath.
• Feelings of having a fast-beating, fluttering or pounding heart.

If you or your child has any of these symptoms within a week of getting a COVID-19 vaccine, seek medical care.

The risk of myocarditis or pericarditis after a COVID-19 vaccine is rare. These conditions have been reported after COVID-19 vaccination with any of the vaccines offered in the United States. Most cases have been reported in males ages 12 to 39.

These conditions happened more often after the second dose of the COVID-19 vaccine and typically within one week of COVID-19 vaccination. Most of the people who got care felt better after receiving medicine and resting.

These complications are rare and also may happen after getting sick with the virus that causes COVID-19. In general, research on the effects of the most used COVID-19 vaccines in the United States suggests the vaccines lower the risk of complications such as blood clots or other types of damage to the heart.

If you have concerns, your healthcare professional can help you review the risks and benefits based on your health condition.

Things to know before a COVID-19 vaccine

Are covid-19 vaccines free.

In the U.S., COVID-19 vaccines may be offered at no cost through insurance coverage. For people whose vaccines aren't covered or for those who don't have health insurance, options are available. Anyone younger than 18 years old can get no-cost vaccines through the Vaccines for Children program.

Can I get a COVID-19 vaccine if I have an existing health condition?

Yes, COVID-19 vaccines are safe for people who have existing health conditions, including conditions that have a higher risk of getting serious illness with COVID-19.

The COVID-19 vaccine can lower the risk of death or serious illness caused by COVID-19. Your healthcare team may suggest that you get added doses of a COVID-19 vaccine if you have a moderately or severely weakened immune system.

Cancer treatments and other therapies that affect some immune cells also may affect your COVID-19 vaccine. Talk to your healthcare professional about timing additional shots and getting vaccinated after immunosuppressive treatment.

Talk to your healthcare team if you have any questions about when to get a COVID-19 vaccine.

Is it OK to take an over-the-counter pain medicine before or after getting a COVID-19 vaccine?

Don't take medicine before getting a COVID-19 vaccine to prevent possible discomfort. It's not clear how these medicines might impact the effectiveness of the vaccines. It is OK to take this kind of medicine after getting a COVID-19 vaccine, as long as you have no other medical reason that would prevent you from taking it.

Allergic reactions and COVID-19 vaccines

What are the signs of an allergic reaction to a covid-19 vaccine.

Symptoms of a life-threatening allergic reaction can include:

If you or a person you're caring for has any life-threatening symptoms, get emergency care right away.

Less serious allergic reactions include a general rash other than where you got the vaccine, or swelling of the lips, face or skin other than where the shot was given. Contact your healthcare professional if you have any of these symptoms.

Tell your healthcare professional about your reaction, even if it went away on its own or you didn't get emergency care. This reaction might mean that you are allergic to the vaccine. You might not be able to get a second dose of the same vaccine. But you might be able to get a different vaccine for your second dose.

Can I get a COVID-19 vaccine if I have a history of allergic reactions?

If you have a history of severe allergic reactions not related to vaccines or injectable medicines, you may still get a COVID-19 vaccine. You're typically monitored for 30 minutes after getting the vaccine.

If you've had an immediate allergic reaction to other vaccines or injectable medicines, ask your healthcare professional about getting a COVID-19 vaccine. If you've ever had an immediate or severe allergic reaction to any ingredient in a COVID-19 vaccine, the CDC recommends not getting that specific vaccine.

If you have an immediate or severe allergic reaction after getting the first dose of a COVID-19 vaccine, don't get the second dose. But you might be able to get a different vaccine for your second dose.

Pregnancy, breastfeeding and fertility with COVID-19 vaccines

Can pregnant or breastfeeding women get the covid-19 vaccine.

The CDC recommends getting a COVID-19 vaccine if:

• You are planning to or trying to get pregnant.
• You are pregnant now.
• You are breastfeeding.

Staying up to date on your COVID-19 vaccine helps prevent severe COVID-19 illness. It also may help a newborn avoid getting COVID-19 if you are vaccinated during pregnancy.

People at higher risk of serious illness can talk to a healthcare professional about additional COVID-19 vaccines or other precautions. It also can help to ask about what to do if you get sick so that you can quickly start treatment.

Children and COVID-19 vaccines

If children don't often experience severe illness with covid-19, why do they need a covid-19 vaccine.

While rare, some children can become seriously ill with COVID-19 after getting the virus that causes COVID-19 .

A COVID-19 vaccine might prevent your child from getting the virus that causes COVID-19 . It also may prevent your child from becoming seriously ill or having to stay in the hospital due to the COVID-19 virus.

After a COVID-19 vaccine

Can i stop taking safety precautions after getting a covid-19 vaccine.

You can more safely return to activities that you might have avoided before your vaccine was up to date. You also may be able to spend time in closer contact with people who are at high risk for serious COVID-19 illness.

But vaccines are not 100% effective. So taking other action to lower your risk of getting COVID-19 still helps protect you and others from the virus. These steps are even more important when you're in an area with a high number of people with COVID-19 in the hospital. Protection also is important as time passes since your last vaccination.

If you are at higher risk for serious COVID-19 illness, basic actions to prevent COVID-19 are even more important. Some examples are:

• Avoid close contact with anyone who is sick or has symptoms, if possible.
• Use fans, open windows or doors, and use filters to move the air and keep any germs from lingering.
• Wash your hands well and often with soap and water for at least 20 seconds. Or use an alcohol-based hand sanitizer with at least 60% alcohol.
• Cough or sneeze into a tissue or your elbow. Then wash your hands.
• Clean and disinfect high-touch surfaces. For example, clean doorknobs, light switches, electronics and counters regularly.
• Spread out in crowded public areas, especially in places with poor airflow. This is important if you have a higher risk of serious illness.
• The CDC recommends that people wear a mask in indoor public spaces if COVID-19 is spreading. This means that if you're in an area with a high number of people with COVID-19 in the hospital a mask can help protect you. The CDC suggests wearing the most protective mask possible that you'll wear regularly, that fits well and is comfortable.

Can I still get COVID-19 after I'm vaccinated?

COVID-19 vaccination will protect most people from getting sick with COVID-19. But some people who are up to date with their vaccines may still get COVID-19. These are called vaccine breakthrough infections.

People with vaccine breakthrough infections can spread COVID-19 to others. However, people who are up to date with their vaccines but who have a breakthrough infection are less likely to have serious illness with COVID-19 than those who are not vaccinated. Even when people who are vaccinated get symptoms, they tend to be less severe than those felt by unvaccinated people.

Researchers continue to study what happens when someone has COVID-19 a second time. Reinfections and breakthrough infections are generally milder than the first infection. But severe illness can still happen. Serious illness is more likely among people older than age 65, people with more than four medical conditions and people with weakened immune systems.

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• Volume 12, Issue 2
• Side effects of COVID-19 vaccines: a systematic review and meta-analysis protocol of randomised trials
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• Kleyton Santos Medeiros 1 , 2 ,
• Ana Paula Ferreira Costa 1 ,
• Ayane Cristine Alves Sarmento 1 ,
• Cijara Leonice Freitas 1 ,
• http://orcid.org/0000-0002-8351-5119 Ana Katherine Gonçalves 3
• 1 Health Sciences Postgraduate Program, Federal University of Rio Grande do Norte , Natal , Rio Grande do Norte , Brazil
• 2 Instituto de Ensino, Pesquisa e Inovação, Liga Contra o Câncer , Natal , Rio Grande do Norte , Brazil
• 3 Department of Obstetrics and Gynecology , Universidade Federal do Rio Grande do Norte , Natal , Brazil
• Correspondence to Dr Ana Katherine Gonçalves; anakatherine_ufrnet{at}yahoo.com.br

Introduction SARS-CoV-2 is responsible for a large number of global COVID-19 cases. Strategies such as social isolation, personal hygiene and frequent hand washing have been implemented; however, a protective vaccine is required to achieve sufficient herd immunity to SARS-CoV-2 infection to ultimately control the COVID-19 pandemic. To meet the urgent need for a vaccine, a reduction in the development schedule has been proposed from 10–15 years to 1–2 years. For this reason, this systematic review and meta-analysis protocol aims to compare the side effects, safety and toxicity of COVID-19 vaccines available globally, including their combinations.

Methods and analysis We will select randomised controlled trial-type studies that evaluate the side effects of the COVID-19 vaccine. PubMed, Web of Science, Embase, CINAHL, PsycINFO, LILACS, SCOPUS, ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), medRxiv.org, biorxiv.org, preprints.org and the Cochrane Library will be searched for eligible studies until December 2021. Three reviewers will independently screen and select studies, assess methodological quality and extract data. A meta-analysis will be performed, if possible, and the Grading of Recommendations, Assessment, Development and Evaluations summary of findings will be presented.

Ethics and dissemination This study will review published data, and thus it is unnecessary to obtain ethical approval. The findings of this systematic review will be published in a peer-reviewed journal.

PROSPERO registration number CRD42021231101.

• adverse events
• clinical trials

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2021-050278

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Strengths and limitations of this study

Four authors (KSM, APFC, ACAS, CLF) will select the articles independently using titles and abstracts.

To the best of our knowledge, there are no existing reviews regarding the side effects of COVID-19 vaccines.

The DerSimonian and Laird method may underestimate the true between-study variance, potentially producing overly narrow CIs for the mean effect. This fact is a limitation, so the collection of studies will be done with care and the assumptions of the analytical methods will be assessed.

Introduction

SARS-CoV-2 is responsible for a large number of global COVID-19 cases. It is a highly transmissible virus among humans that has become a significant public health issue. 1 Symptoms include fever, dry cough, fatigue, shortness of breath, chills, muscle pain, headache, gastric disorders and weight loss, often leading to death. 2

Strategies such as social isolation, personal hygiene and frequent hand washing have been implemented; however, a protective vaccine is required to achieve sufficient herd immunity to SARS-CoV-2 infection to ultimately control the COVID-19 pandemic. 3 To meet the urgent need for a vaccine, a reduction in the development schedule has been proposed from 10–15 years to 1–2 years. 4

SARS-CoV-2 is an RNA virus with a high mutation rate, and that on the envelope surface has three important structural proteins that can be identified: spike protein (S), envelope protein (E) and membrane protein (M). Most innovative vaccines have focused their efforts on inducing an immune response against the S protein. Attenuated virus vaccines are based on weakened microorganisms, effective in stimulating the immune system. The inactivated ones (dead microorganisms) are more stable than the attenuated ones, but they have a short duration of immunological memory that requires the association of adjuvants. mRNA vaccines are stable—and can be easily produced in large quantities. Vaccines against COVID-19 differ in composition and mechanism of action, which may be relevant for their safety and efficacy, being essential for the success and eradication of this infection. 5 6 The viral vector (mRNA) vaccine encodes full-length S protein ectodomains of SARS-CoV-2, which contains both T and B cell epitopes that can induce cellular and humoral immune responses against viral infection. 7

Assessing the safety, efficacy and side effects of the vaccine is urgently needed, and has been heavily scrutinised by the leading medical agencies around the world, like the Centers for Disease Control and Prevention and the Food and Drug Administration. Developing any vaccine needs to ensure that safety risks are identified and quantified against potential benefits. Among the potential risks raised in the context of COVID-19, vaccine development is the security and effectiveness of immune responses elicited by a vaccine. Here, this systematic review protocol aims to assess the side effects, safety and toxicity of vaccines against COVID-19.

This systematic review and meta-analysis protocol aims to compare the side effects, safety and toxicity of COVID-19 vaccines available globally, including their combination.

Review question

What are the rates of adverse reactions (local and systemic) to COVID-19 vaccines?

Methods and analysis

The meta-analysis protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. 8 9 This protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO).

Eligibility criteria

The inclusion criteria involved: (1) randomised controlled trial (RCT)-type studies that evaluated the side effects of the COVID-19 vaccine; (2) experiments involving human beings; (3) studies evaluating the safety, immunogenicity and efficacy parameters of the vaccines; (4) studies that presented similar vaccination protocols; (5) studies published since January 2020 until December 2021; and (6) studies published in any language.

The exclusion criteria were as follows: (1) observational studies, and (2) case reports, meeting abstracts, review papers and commentaries.

Patients, intervention, comparison, outcome strategy and types of studies

Patients: healthy adults aged 18 years or older who were HIV negative and previously SARS-CoV-2 infection free.

Intervention: COVID-19 vaccine or a combination of vaccines against COVID-19.

Comparator/control: placebo.

Outcome: safety, tolerability and immunogenicity of the COVID-19 vaccine or the combination of vaccines against COVID-19.

Types of studies: RCTs.

Information sources

The following databases will be searched: Medline / PubMed, Web of Science, Embase, CINAHL, PsycINFO, Latin American and Caribbean Health Sciences Literature (LILACS), SCOPUS, ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), medRxiv.org, biorxiv.org, preprints.org and Cochrane Central Controlled Trials Registry. Furthermore, eligible studies may also be selected from the reference lists of retrieved articles.

Patient and public involvement

The individual patient data will not be presented. A literature search will be carried out from defined databases. No patient will be involved in the study planning and application process during neither the analysis nor the dissemination of results.

Search strategy

Our keyword search will be based on Medical Subject Headings according to the following combination: (COVID-19 OR SARS-CoV-2 OR 2019-nCoV OR coronavirus) AND (vaccines OR vaccination OR COVID-19 vaccine OR SARS-CoV-2 vaccine OR BNT162 vaccine OR mRNA-1273 vaccine OR COVID-19 aAPC vaccine OR INO-4800 vaccine OR LV-SMENP-DC COVID-19 vaccine OR Ad5-nCoV vaccine OR ChAdOx1 COVID-19 vaccine OR MNA SARS-CoV-2 S1 subunit vaccines OR PittCoVacc OR Inactivated novel coronavirus 2019-CoV vaccine Vero cells OR Inactivated Vaccines OR SARS-CoV-2 inactivated vaccines OR Viral Vaccines OR Gam-COVID-Vac vaccine OR Ad26.COV2.S vaccine OR EpiVacCorona vaccine) AND (Toxicity OR Vaccine Immunogenicity OR side effects OR adverse events) AND (randomized controlled trial OR double blind method OR clinical trial) ( table 1 ). A list of vaccines available at WHO was also used.

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Medline search strategy

Study records

Four researchers (KSM, APFC, ACAS, CLF) performed the selection of the studies of interest. Titles and abstracts will be read independently, and duplicate studies will be excluded. The same authors analysed the selected texts to assess the compliance with the inclusion criteria. A fifth reviewer, AKG, solves the discrepancies. The flow chart of this study is shown in figure 1 .

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Flow diagram of the search for eligible studies on the side effects, safety and toxicity of the COVID-19 vaccine. CENTRAL, Cochrane Central Register of Controlled Trials.

Data collection process and management

A standardised data extraction form was developed and tested. Data from each included study will be extracted independently by two reviewers (ACAS and APFC), and any subsequent discrepancies will be resolved through discussion with a third reviewer (AKG). The data extracted will include information on authors, the year of publication, study location, type of study, main objectives, population, type of vaccine, follow-up of participants, rates of systemic events, gastrointestinal symptoms, injection site-related adverse effects and serious vaccine-related adverse events ( table 2 ). Furthermore, participant characteristics (eg, mean age, gender) and results for immunogenicity will be collected.

Adverse events of COVID-19 vaccines

The study authors will be contacted in case of missing data and/or to resolve any uncertainties. In addition, any additional information will be recorded. All data entries will be checked twice. If we find a set of articles with similar characteristics based on the information in the data extraction table, we will perform a meta-analysis using a random-effects model. If there are data that are not clear in some articles, the corresponding author will be contacted for possible clarification.

Risk of bias in individual studies

Three authors (KSM, ACAS, APFC) will independently assess the risk of bias in the eligible studies using the Cochrane risk-of-bias tool. 10 The Risk of Bias 2 tool 11 will be used to assess the risk of bias. Bias is assessed as a judgement (high, low or unclear) for individual elements from five domains (selection, performance, attrition, reporting and others).

Data will be entered into the Review Manager software (RevMan V.5.2.3). This software allows the user to enter protocols; complete reviews; include text, characteristics of the studies, comparison tables and study data; and perform meta-analyses. For dichotomous outcomes, we extracted or calculated the OR and 95% CI for each study. In case of heterogeneity (I 2 ≥50%), the random-effects model will be used to combine the studies to calculate the OR and 95% CI using the DerSimonian-Laird algorithm 12 .

Data synthesis and analysis

To grade the strength of evidence from the included data, we will use the Grading of Recommendations, Assessment, Development and Evaluation 13 approach. The summary of the assessment will be incorporated into broader measurements to ensure the judgement of the risk of bias, consistency, directness and precision. The quality of the evidence will be assessed based on the risk of bias, indirectness, inconsistency, imprecision and publication bias.

The COVID-19 pandemic represents one of the most significant global public health crises of this generation. Lockdown, quarantine, contact tracing and case isolation are suggested as effective interventions to control the epidemic; however, they may present different results in different contexts because of the specific features of the COVID-19. The lack of implementation of continued interventions or effective treatments further contributes to discovering and using effective and safe vaccines. 14 15

For all these reasons, scientists worldwide entered a race to find a vaccine candidate useful in fighting the new coronavirus pandemic. Nevertheless, it is essential to note that a vaccine’s production is not easy and quick. Before being released to the population, a vaccine must go through three phases of clinical trials that prove its safety and effectiveness. More volunteers are recruited at each stage, and the researchers analyse the test results to ensure that a vaccine can be licensed. 16–18

One hundred and seventy-three vaccines were in preclinical development and 64 in clinical trials until 20 January 2021. On 31 December 2020, the WHO listed the mRNA vaccine against COVID-19 for emergency use, making this Pfizer/BioNTech immuniser the first to receive WHO emergency validation from the beginning outbreak. Already, in January 2021, emergency approval was granted to nine vaccines by regulatory authorities in different parts of the world. 14 19

With the starting vaccination, several studies were carried out to ascertain the safety of these vaccines, since they were produced in record time. 20–22 Currently, one systematic review about the thematic showed that of 11 published clinical trials of COVID-19 vaccines included in the study, adverse reactions reported were considered mild to moderate with few severe reactions which were unrelated to the test vaccine. Common adverse events were pain at the site of injection, fever, myalgia, fatigue and headache. Serious adverse events (SAE) were reported in four trials: COVID-19 Vaccine AstraZeneca (AZD1222)—168 SAEs with only three related to the vaccine; Ad26.COV2.S—four with none related to the testing vaccine; five with Comirnaty (BNT162b1) vaccine and one with Covaxin (BBV152) vaccine. 19

One limitation about the COVID-19 vaccine safety tested until now is that clinical trials of the safety and effectiveness have had low inclusion of vulnerable groups, for example, older persons, the first population to receive the whole vaccine. That’s why pharmacovigilance postmarketing is necessary to surveillance of new drugs, as a critical aspect of evaluating medicine safety and effectiveness, particularly in risk groups.

Other prevention approaches are likely to emerge in the coming months, including antiviral agents, drugs may be to decrease disease progression, monoclonal antibodies, hyperimmune globulin and convalescent titre. If proven effective, these approaches could be used in high-risk individuals, including healthcare workers, other essential workers and older adults. 23–26 It is essential to maintain protective measures such as washing hands frequently with soap and water or gel alcohol and covering the mouth with a forearm when coughing or sneezing.

For all the reasons mentioned above, this review is necessary and essential. The latter is a well-defined protocol registered with PROSPERO, well planned to include the largest possible number of vaccines, a significant number of vaccinated patients, thus providing safe and reliable results regarding the use of vaccines.

Ethics and dissemination

This study will review published data, and thus it is unnecessary to obtain ethical approval. The findings of this systematic review will be published in a peer-reviewed journal.

Ethics statements

Patient consent for publication.

Not applicable.

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KSM and APFC are joint first authors.

Contributors KSM, ACAS and APFC contributed to the design of this review. KSM and ACAS drafted the protocol manuscript. APFC and AKG revised the manuscript. KSM, AKG and APFC developed the search strategies. KSM, CLF and ACAS implemented the search strategies. KSM, CLF, ACAS and APFC tracked the potential studies, extracted the data and assessed the quality. In case of disagreement between the data extractors, AKG advised on the methodology and worked as a referee. KSM completed the data synthesis. All authors approved the final version for publication.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

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